Novel process for the preparation of esomeprazole and salts thereof

ABSTRACT

A novel process for the preparation of omeprazole and its enantiomers, such as esomeprazole, as well as the preparation of related 2-(2-pyridinylmethyl-sulphinyl)-1H-benzimidazoles, including pantoprazole, lansoprazole and rabeprazole, as recemates or single enantiomers, and their alkali or alkaline salts has been developed. The novel process involves the surprising discovery that protection of the free-base benzimidazole sulfoxide (e.g. omeprazole or esomeprazole), by reaction with an alkyl, aryl or aralkyl chloroformate following oxidation of the corresponding sulfide, eliminates the need for its direct isolation. Subsequent removal of the protecting group with a solution of alkali or alkaline earth alkoxide in a C1-C4 alcohol directly provides the corresponding salt. By eliminating the need to handle the free-base benzimidazole sulfoxide, this advantageous procedure provides increased chemical yields over processes described in the art.

REFERENCE TO CO-PENDING APPLICATION

This application is a continuation-in-part of application Ser. No.11/449,707 filed on Jun. 9, 2006.

FIELD OF THE INVENTION

The present invention relates to a novel process for preparingesomeprazole, or the enantioselective preparation of single enantiomersof related 2-(2-pyridinylmethyl-sulphinyl)-1H-benzimidazoles, includingpantoprazole, lansoprazole and rabeprazole, and pharmaceuticallyacceptable alkali and alkaline earth salts thereof. The presentinvention may also be used as an alternative method of preparation forracemic 2-(2-pyridinylmethyl-sulphinyl)-1H-benzimidazoles, includingomeprazole, pantoprazole, lansoprazole, and rabeprazole, when achiraloxidation reactions are used.

BACKGROUND OF THE INVENTION

Esomeprazole magnesium 1, the (S)-enantiomer of the proton pumpinhibitor omeprazole, was developed by AstraZeneca as asecond-generation of Prilosec®, and is currently marketed as Nexium®.

Esomeprazole is effective for the treatment of conditions such asstomach and duodenal ulcers, gastroesophageal reflux disease, andZollinger-Ellison syndrome. Its mode of action is as a proton pumpinhibitor, thereby reducing gastric acid levels in the stomach,permitting the stomach and esophagus to heal.

Chemically known as(T-4)-Bis[5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolato]magnesium(1), esomeprazole magnesium can be prepared through processes known inthe art.

Sigrist-Nelson et al. (Eur. J. Biochem. 1987, 166, 453-459) preparedoptically active benzimidazole sulfoxides, with structural similaritiesto omeprazole, using the procedure of Pitchen et al. (J. Am. Chem. Soc.1984, 160, 8188-8193). While the enantiomeric excesses reported werelower than those achieved by Pitchen et al., later work (Zhao, S. H. etal. Tetrahedron 1987, 43, 5135-5144) demonstrated that changes to thereaction conditions could offer improved results.

For instance, U.S. Pat. No. 5,948,789 discloses a process that involvesan asymmetric oxidation of sulfide 2 with an enantiomeric excess of 87%.The optical purity of sulfoxide 1a could be then improved viarecrystallization of the sodium analog of 1. However, this processsuffers from various deficiencies including low (less than 50% onaverage) chemical yield.

Another method to prepare optically pure sulfoxide 1 employs resolutionof a racemic mixture of the sulfoxide. For instance, WO 95/32957 teachesa method to obtain optically pure sulfoxide 1a in neutral form byseparation of a diastereomeric mixture by chromatography followed byremoval of the derivatizing agent. This process involves multiple stepsand is not practical for industrial scale.

WO 92/08716 discloses a process to prepare enantiomerically purepantoprazole, a structurally similar antiulcer drug developed by BYKGmbH, and enantiomerically pure (+)-omeprazole, which could also beadapted for esomeprazole (1a). This process is similar to WO '957 inwhich different diastereomers of the sulfoxide derivatives are separatedby re-crystallization. Again this process requires multiple stepsresulting in a low yield.

U.S. Pat. No. 5,929,244 by Astra reveals a process for the purificationof an enantiomerically enriched sulfoxide mixture by re-crystallizationin various organic solvents. This process is easy to operate butrequires several re-crystallizations to achieve the requisiteenantiomeric purity for use as a pharmaceutical.

In WO 03/089408, Sun Pharmaceutical discloses a similar process to US'789 in which chiral methyl mandelate is used followed by formation of achiral Ti(IV) complex. The process suffers the same drawbacks as before,for example, additional chemical operations and low (less than 50%)yield.

US 2004/077869 discloses a novel process to produce optically puresulfoxide 1a in neutral form in which the racemic or enantiomericallyenriched sulfoxide is resolved by formation of a Ti(IV) complex using aTi(OiPr)₄/diethyl D-tartrate/L-mandelic acid system. This multi-stepprocess is relatively complex, laborious, and low yielding.

U.S. Pat. No. 5,039,806, by AB Hassle, discloses the racemic preparationof derivatives 3 by either acylation of the sulfoxide or acylation ofthe corresponding sulfide, followed by oxidation. However, when comparedto the present process, the chemical yields are low.

Therefore, an object of the invention is to provide a facile andcommercially viable process to produce esomeprazole (1a), and itspharmaceutically acceptable alkali and alkaline earth salts, whichovercomes some of the disadvantages of the prior art by providing anincreased yield and a process that avoids isolating the unstableesomeprazole as an intermediate.

Similarly, an object of the invention is to provide a facile andcommercially viable process to produce omeprazole, and itspharmaceutically acceptable alkali and alkaline earth salts, whichovercomes some of the disadvantages of the prior art by providing anincreased yield and a process that avoids isolating the unstableomeprazole as an intermediate.

EP 0 005 129, by AB Hassle, discloses the preparation of omeprazole, andother related benzimidazoles, via oxidation of the corresponding sulfidewith meta-chloroperbenzoic acid. This procedure results in the isolationof the free-base of omeprazole.

EP 0 124 495, by AB Hassle, discloses the preparation of various saltsof omeprazole, including sodium and magnesium, however, the processutilizes the free-base of omeprazole, making it unattractive for use onan industrial scale.

Further and other objects of the invention will become apparent to thoseskilled in the art when considering the following summary of theinvention and a more detailed description of the preferred embodimentscontained herein.

SUMMARY OF THE INVENTION

It has been unexpectedly and surprisingly discovered that esomeprazolecould be prepared using a straightforward, robust and scalable processthat is convenient and effective. This novel process is depicted inScheme 1 for the preparation of esomeprazole (1a) and its alkali metaland alkaline earth salts (1b). It has also been discovered that if asolution of an alkali metal alkoxide or alkaline earth metal alkoxide ina C1 to C4 alkyl alcohol is employed in the decarbamoylation step, thecorresponding salt of esomeprazole can be prepared directly. In thisinstance, it is advantageous in that it avoids isolation and handling ofthe esomeprazole free base, thus leading to an enhanced chemical yieldover procedures described in the art.

In one aspect of the invention there is provided a process to prepareesomeprazole or alkali and alkaline earth metal salts thereof. The saidprocess comprises the following steps:

-   -   (1) enantioselectively oxidizing the prochiral sulfide        2,2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole        to the corresponding sulfoxide using an asymmetric oxidation        method,    -   (2) acylating with an alkyl, aryl, or aralkyl chloroformate at        the N-atom of the benzimidazole ring to produce        enantiomerically-enriched derivatives 3 (R=alkyl, aryl or        aralkyl),    -   (3) mixing the enantiomerically-enriched derivatives 3 with:        -   (a) a C1 to C4 alkyl alcohol, or        -   (b) a solution of an alkali metal alkoxide in a C1 to C4            alkyl alcohol, or    -   (c) a solution of an alkaline earth metal alkoxide in a C1 to C4        alkyl alcohol, and,    -   (4) isolating the corresponding esomeprazole in its neutral form        by precipitation by concentration and/or addition of an        anti-solvent(s) or spray drying; or isolation as an alkali metal        salt or an alkaline earth metal salt by precipitating by        concentration and/or addition of an anti-solvent(s) or spray        drying the solution.

In another aspect of the invention the N-atom of the benzimidazole ringof the enantiomerically enriched sulfoxide is protected with aprotecting group selected from alkoxycarbonyl, aryloxycarbonyl oraralkoxycarbonyl to form enantiomerically-enriched N-protectedderivatives 3. Preferably, the protecting group is tert-butoxycarbonylor benzyloxycarbonyl.

In yet another aspect of the invention there are provided theenantiomerically-enriched N-protected compounds 3.

In yet another aspect of the invention there are provided esomeprazoleor its alkali or alkaline earth metal salts from theenantiomerically-enriched compounds of formula 3 in a one-pot mannerusing a C1 to C4 alkyl alcohol or together with an alkali metalalkoxide, or with an alkaline earth metal alkoxide. Preferably thealcohol is methanol, ethanol or iso-propanol. More preferably thealcohol is methanol. Preferably the alkali metal or alkaline earth saltis magnesium, sodium, potassium, lithium, or calcium. More preferably,the alkali metal or alkaline earth salt is sodium or magnesium.

In yet another aspect of the invention there are provided solutionscontaining esomeprazole in a C1 to C4 alkyl alcohol by directly addingthe derivatives 3 to the C1 to C4 alkyl alcohol. Preferably the alcoholis methanol, ethanol or iso-propanol. More preferably the alcohol ismethanol.

In yet another aspect of the invention there is provided a solutioncontaining esomeprazole alkali metal salt in a C1 to C4 alkyl alcohol bydirectly adding the enantiomerically-enriched derivatives 3, preferablyin a quantity of about 1 mole of esomeprazole per mole of alkali metal,to a solution of alkali metal alkoxide in a C1 to C4 alkyl alcohol.Preferably the alcohol is methanol, ethanol or iso-propanol. Morepreferably the alcohol is methanol. Preferably the alkali metal oralkaline earth salt is magnesium, sodium, potassium, lithium, orcalcium. More preferably, the alkali metal or alkaline earth salt issodium or magnesium.

In yet another aspect of the invention there are provided solutionscontaining esomeprazole alkaline earth metal salt in a C1 to C4 alkylalcohol by directly adding the enantiomerically-enriched derivatives 3,preferably in a quantity of about 2 moles of esomeprazole per mole ofalkaline earth metal, to solutions of alkaline earth metal alkoxide in aC1 to C4 alkyl alcohol. Preferably the alcohol is methanol, ethanol oriso-propanol. More preferably the alcohol is methanol. Preferably thealkali metal or alkaline earth salt is magnesium, sodium, potassium,lithium, or calcium. More preferably, the alkali metal or alkaline earthsalt is sodium or magnesium.

In yet another aspect of the invention there is provided esomeprazole orits salts by adding anti-solvents to an optionally concentratedalcoholic solutions containing esomeprazole, esomeprazole alkali metalsalt or esomeprazole alkaline earth metal salt. These anti-solventsinclude C1 to C3 alkyl acetates such as ethyl acetate and C4 to C8 alkylethers such as methyl t-butyl ether (MTBE), diethyl ether anddiisopropyl ether, and a C6 to C9 hydrocarbon such as hexane of heptane,or mixtures thereof. The most preferable anti-solvents are ethyl acetateand MTBE. Preferably the alcohol is methanol, ethanol or iso-propanol.More preferably the alcohol is methanol. Preferably the alkali metal oralkaline earth salt is magnesium, sodium, potassium, lithium, orcalcium. More preferably, the alkali metal or alkaline earth salt issodium or magnesium.

In yet another aspect of the invention there is provided a simple,scalable, and industrially applicable process that provides esomeprazolein high optical yield and a higher chemical yield than is currentlyavailable in the art.

In yet another aspect of the invention there are provided processes forthe preparation of amorphous esomeprazole or its salts.

Owing to the structural similarities of other benzimidazoles sulfoxides,such as lansoprazole (4), pantoprazole (5) and rabeprazole (6), amongothers, each of which contains a chiral centre about the sulfur atom,

a further aspect of the invention would be the use of the aboveprocesses in the preparation either optical isomer of compounds offormula (I):

wherein

-   -   ring A is a benzene ring optionally having 1 to 3        substituent(s), which may be the same or different, are each        independently selected from (a) a halogen atom, (b) a cyano, (c)        a nitro, (d) an alkyl optionally having 1 to 3 substituent(s)        selected from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxy        carbonyl and a carbamoyl, (e) an alkoxy optionally having 1 to 3        substituent(s) selected from a halogen atom, a C₁₋₆ alkoxy, a        C₁₋₆ alkoxycarbonyl and a carbamoyl, (f) an aryl, (g) an        aryloxy, (h) an acyl, (i) an acyloxy and (j) a 5- to 10-membered        heterocyclic group,    -   R¹, R² and R³ are each a hydrogen atom; an alkyl group        optionally having 1 to 3 substituent(s) selected from a halogen        atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and a carbamoyl; an        alkoxy group optionally having 1 to 3 substituent(s) selected        from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and a        carbamoyl; or a di-C₆₋₁₄ arylamino, and    -   * is an asymmetric center,        and their corresponding pharmaceutically acceptable alkali and        alkaline earth metal salts.

As would be understood by the person skilled in the art, a chiraloxidation process, such as the one described in U.S. Pat. No. 5,948,789,may be used to produce a product consisting of either optical isomerdepending on the chirality of the chiral auxiliary used. As such, afurther aspect of the invention is a process that would allow for thepreparation of either optical isomer of the desired benzimidazole, forexample, (R)— or (S)-omeprazole.

A further aspect of the present invention is the use of theoxidation/protection/deprotection process in the preparation of racemicmixtures of 2-(2-pyridinylmethyl-sulphinyl)-1H-benzimidazoles such asomeprazole (see Scheme 2), pantoprazole, lansoprazole and rabeprazole orother compounds of Formula (I). Under these circumstances the proceduredescribed below is employed. One example of such an achiral oxidationprocess would utilize meta-perchlorobenzoic acid as has been previouslydescribed in the art (EP 0 005 129).

The said process comprises the following steps where the desired productis omeprazole:

-   -   (1) oxidizing the sulfide        2,2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole        to the corresponding sulfoxide using a suitable oxidation        method,    -   (2) acylating with an alkyl, aryl, or aralkyl chloroformate at        the N-atom of the benzimidazole ring to produce derivatives 7        (R=alkyl, aryl or aralkyl),    -   (3) mixing the derivatives 7 with:        -   (a) a C1 to C4 alkyl alcohol, or        -   (b) a solution of an alkali metal alkoxide in a C1 to C4            alkyl alcohol, or        -   (c) a solution of an alkaline earth metal alkoxide in a C1            to C4 alkyl alcohol, and,    -   (4) isolating the corresponding omeprazole in its neutral form        by precipitation by concentration and/or addition of an        anti-solvent(s) or spray drying; or isolation as an alkali metal        salt or an alkaline earth metal salt 8 by precipitating by        concentration and/or addition of an anti-solvent(s) or spray        drying the solution.

In another aspect of the invention the N-atom of the benzimidazole ringof the sulfoxide is protected with a protecting group selected fromalkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl to form racemicN-protected derivatives 7. Preferably, the protecting group istert-butoxycarbonyl or benzyloxycarbonyl.

In yet another aspect of the invention there are provided omeprazole orits alkali or alkaline earth metal salts from the racemic compounds offormula 7 in a one-pot manner using a C1 to C4 alkyl alcohol or togetherwith an alkali metal alkoxide, or with an alkaline earth metal alkoxide.Preferably the alcohol is methanol, ethanol or iso-propanol. Morepreferably the alcohol is methanol. Preferably the alkali metal oralkaline earth salt is magnesium, sodium, potassium, lithium, orcalcium. More preferably, the alkali metal or alkaline earth salt issodium or magnesium.

In yet another aspect of the invention there are provided solutionscontaining omeprazole in a C1 to C4 alkyl alcohol by directly adding thederivatives 7 to the C1 to C4 alkyl alcohol. Preferably the alcohol ismethanol, ethanol or iso-propanol. More preferably the alcohol ismethanol.

In yet another aspect of the invention there is provided a solutioncontaining omeprazole alkali metal salt in a C1 to C4 alkyl alcohol bydirectly adding the racemic derivatives 7, preferably in a quantity ofabout 1 mole of omeprazole per mole of alkali metal, to a solution ofalkali metal alkoxide in a C1 to C4 alkyl alcohol. Preferably thealcohol is methanol, ethanol or iso-propanol. More preferably thealcohol is methanol. Preferably the alkali metal or alkaline earth saltis magnesium, sodium, potassium, lithium, or calcium. More preferably,the alkali metal or alkaline earth salt is sodium or magnesium.

In yet another aspect of the invention there are provided solutionscontaining omeprazole alkaline earth metal salt in a C1 to C4 alkylalcohol by directly adding the racemic derivatives 7, preferably in aquantity of about 2 moles of omeprazole per mole of alkaline earthmetal, to solutions of alkaline earth metal alkoxide in a C1 to C4 alkylalcohol. Preferably the alcohol is methanol, ethanol or iso-propanol.More preferably the alcohol is methanol. Preferably the alkali metal oralkaline earth salt is magnesium, sodium, potassium, lithium, orcalcium. More preferably, the alkali metal or alkaline earth salt issodium or magnesium.

In yet another aspect of the invention there is provided omeprazole orits salts by adding anti-solvents to an optionally concentratedalcoholic solutions containing omeprazole, omeprazole alkali metal saltor omeprazole alkaline earth metal salt. These anti-solvents include C1to C3 alkyl acetates such as ethyl acetate and C4 to C8 alkyl etherssuch as methyl t-butyl ether (MTBE), diethyl ether and diisopropylether, and a C6 to C9 hydrocarbon such as hexane of heptane, or mixturesthereof. The most preferable anti-solvents are ethyl acetate and MTBE.Preferably the alcohol is methanol, ethanol or iso-propanol. Morepreferably the alcohol is methanol. Preferably the alkali metal oralkaline earth salt is magnesium, sodium, potassium, lithium, orcalcium. More preferably, the alkali metal or alkaline earth salt issodium or magnesium.

In yet another aspect of the invention there is provided a simple,scalable, and industrially applicable process that provides omeprazole.

In yet another aspect of the invention there are provided processes forthe preparation of amorphous omeprazole or its salts.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of 3 is typically achieved by the enantioselectiveoxidation of sulfide 2 by any known method in the art, such as theprocedure described in U.S. Pat. No. 5,948,789, followed by reactionwith an alkyl, aryl or aralkyl chloroformate in the presence of a base,such as triethylamine to form crystalline compounds 3. Surprisingly, itwas discovered that derivatives of 3 were readily isolable andpurifiable, making the process efficient and practical for industrialscale.

The reaction of the sulfoxide intermediate with the alkyl, aryl oraralkyl chloroformate is achieved in a suitable organic solvent, mostpreferably a C1 to C3 chlorinated hydrocarbon such as dichloromethane ora C3 to C6 dialkyl ketone such as methyl isobutyl ketone. This reactionis performed at about −5 to about 30° C. and in the presence of analkylamine base such as triethylamine. The stoichiometry of both thebase and the chloroformate reagent is about 1.0 to 3.0 equivalents perequivalent of 2. The products 3 are extracted into a suitable organicsolvent, such as ethyl acetate or another C3 to C6 alkyl ester, andprecipitated by concentration of the organic solvent and/or addition ofan anti-solvent. Examples of suitable anti-solvents include C6 to C9hydrocarbons such as hexane or heptane. The most preferred anti-solventis heptane.

Preferred chloroformates for use in the formation of 3 would becomprised of substituted or unsubstituted C1-C6 alkyl groups,substituted or unsubstituted C6-C9 aryl groups, or unsubstituted C7-C10aralkyl groups. More preferred chloroformates would be comprised ofbenzyl or tert-butyl groups.

In another aspect of the invention, it has been found that whencompounds 3 are treated with a C1 to C4 alkyl alcohol such as methanol,surprisingly, the N-protecting group is easily removed. Afterconcentrating the alcoholic solution and/or addition of an anti-solvent,pure esomeprazole is precipitated and isolated by filtration.

It has been also found that the above process is also suitable forpreparing alkali or alkaline earth salts of esomeprazole. Thus, theN-protected compounds 3 are treated with a solution of alkali oralkaline earth metal alkoxide in a C1 to C4 alkyl alcohol. The mostpreferred alcohol is methanol. The esomeprazole salt is isolated byconcentration of the solution followed by the optional addition of ananti-solvent and/or by spray drying.

The esomeprazole salts prepared by this process can be anypharmaceutically acceptable alkali or alkaline earth metal salts.Preferably, the counter-ion would be an alkali or alkaline earth metal,selected from one of Li, Na, K, Ca or Mg. Most preferably the alkali oralkaline earth metal would be selected from sodium or magnesium, withthe most preferable amount of the alkali or alkaline earth metalalkoxide being about 1 or 0.5 equivalents, respectively, relative toesomeprazole. The reaction temperature is from about −20° C. torefluxing temperature, preferably 0 to 25° C. Preferred C1 to C4 alkylalcohols include methanol, ethanol, iso-propanol, n-propanol, andn-butanol, with the most preferred alcohol being methanol.

If a desired polymorph or amorphous form needs to be prepared, a personskilled in the art could make it accordingly. For example, if anamorphous form of the salt is required, an anti-solvent or anti-solventscould be added into the reaction mixture to precipitate the product inits amorphous form. The anti-solvents are organic solvents such as C4 toC8 alkyl ethers and C1 to C3 alkyl acetates, but not limited as such, inwhich the product has limited solubility. Similarly, other polymorphsknown in the prior art can be prepared accordingly.

The following non-limiting examples further illustrate the manner ofcarrying out the inventive process described herein.

EXAMPLE 1 Preparation of(S)-5/6-methoxy-1-benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

To a solution of2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole2 (10 g) in 50.0 mL toluene under an inert atmosphere, was added(D)-diethyl tartrate (2.75 g). The mixture was heated to 50-55° C. andstirred for 30 minutes. Titanium (IV) isopropoxide (1.73 g) was addedand the temperature was maintained at 50-55° C. for an additional 60minutes. The reaction mixture was cooled to 0-5° C. whereupondiisopropylethylamine (1.33 g) and 80% cumene hydroperoxide (6.93 g)were added while keeping the temperature below 10° C. The reactionmixture was stirred at 0-10° C. for 2-4 hours until the reaction wascomplete. The reaction mixture was warmed to room temperature, filteredthrough Celite and extracted with 12-14% ammonium hydroxide. The aqueousand methyl isobutyl ketone (MIBK, 30 mL) phases were cooled to 0-5° C.The pH was adjusted to 7.3 to 7.8 with acetic acid and phases wereseparated. The aqueous phase was extracted with MIBK. The combinedorganic phases were washed with brine and vacuum distilled to 40 mL togive a solution of(S)-(−)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole in MIBK. The sulfoxide solution was dilutedwith dichloromethane (30 mL) and triethylamine (4.61 g). The mixture wascooled to 0-10° C. and 95% benzyl chloroformate (6.0 g) was added whilekeeping the temperature below 10° C. After stirring for 1-4 hours, water(30 mL) and ethyl acetate (30 mL) were added. The phases were separatedand the aqueous phase was extracted with ethyl acetate. The combinedorganic phases was washed with brine and saturated sodium bicarbonate,vacuum distilled to 30 mL and filtered through Celite™. The filtrate wasstirred while 80 mL of heptanes was added dropwise whereupon thesuspension was cooled to 0-5° C. and maintained at this temperature for1-2 hours. The suspension was filtered, washed with heptanes/ethylacetate (4/1) and dried under vacuum at room temperature to afford(S)-5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.Weight: 11.5 g. Purity: 99% by HPLC. Chiral purity: 99.5% (S-form) byHPLC. Ratio of 5- and 6-methoxy products: ˜1:1. The analytical data wereconsistent with the assigned structure.

H-NMR (400 MHz, CDCl3):

5-Methoxy isomer: δ/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.76(3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.54 (2H, s), 6.95-7.01 (1H, m),7.38 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.68 (1H, d,J=9 Hz), 8.05 (1H, s);

6-Methoxy isomer: 6/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.83(3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.53 (2H, s), 6.95-7.01 (1H, m),7.29 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.75 (1H, d,J=9 Hz), 8.05 (1H, s).

EXAMPLE 2 Preparation of Amorphous Esomeprazole Magnesium Salt (1)

Magnesium metal (0.26 g) was added to methanol (60 mL) and stirred atroom temperature for 3-4 hours. To the mixture was added(S)-5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(10 g ˜1:1 of 5- and 6-methoxy compounds) in portions. After stirringfor 20-30 minutes the methanol was evaporated to a small volume andethyl acetate was added, which caused precipitation. The damp cakeobtained by filtration was pulped in ethyl acetate for 2-3 hours. Thecake obtained by filtration was vacuum-dried to afford optically pureesomeprazole magnesium salt. X-ray powder diffraction patterndemonstrated the amorphous nature of the product. Weight: 7.1 g (75%overall yield). Purity: 99.3% by HPLC. Chiral purity: 99.2% (S-form) byHPLC. Mg content: 3.4%. Analytical data were consistent with that fromthe prior art.

EXAMPLE 3 Preparation of5/6-methoxy-1benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

To a solution of5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole(30 g) in dichloromethane (165 mL) at 0-5° C., under an inertatmosphere, was added meta-chloroperbenzoic acid (0.95 eq) over 10minutes. The mixture was stirred for 10-15 minutes. To the reaction wasadded 12% ammonium hydroxide (180 mL). The layers were separated. Theorganic layer was extracted with 12% ammonium hydroxide (2×180 mL). Thecombined aqueous layers were washed with toluene (90 mL). To the aqueouslayer was added dichloromethane (120 mL) and the mixture was cooled to0-5° C. The pH was adjusted to pH=8.5-9.5 using 50% aqueous acetic acid.The layers were separated. The aqueous layer was extracted withdichloromethane (2×90 mL). The combined organic layers were washed withbrine (30 mL), dried over sodium sulfate, filtered through celite andvacuum distilled to 150 mL to give a solution of5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]1H-benzimidazolein dichloromethane.

The sulfoxide solution was treated with triethylamine (25.4 mL). Themixture was cooled to 0-10° C. and 95% benzyl chloroformate (13.5 g) indichloromethane (30 mL) was added while keeping the temperature below10° C. After stirring for 2-3 hours, water (90 mL) was added. The phaseswere separated and the aqueous phase was extracted with dichloromethane(60 mL). The combined organic phases were washed with brine (60 mL) andsaturated sodium bicarbonate (30 mL) and vacuum distilled to 90 mL.Ethyl acetate (180 mL) was added to the solution and vacuumed distilledto 90 mL. The solution was stirred while 150 mL of heptanes was added at20-25° C. The suspension was cooled to 0-5° C. and maintained at thistemperature for 2-3 hours. The suspension was filtered and the damp cakewas pulped in ethyl acetate (30 mL) and heptanes (120 mL) for 1-2 hours.The suspension was filtered, washed with heptanes/ethyl acetate (4/1)(2×30 mL) and dried under vacuum at room temperature to afford5/6-methoxy-1-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.Weight: 25.91 g. Yield: 59%. Ratio of 5- and 6-methoxy products: 3:2.The analytical data was consistent with the assigned structure.

¹H-NMR (300 MHz, CDCl3):

5-Methoxy isomer: δ/ppm=2.19 (3H, s), 2.33 (3H, s), 3.74 (3H, s), 3.77(3H, s), 4.68 (2H, dd, J=13, 29 Hz), 5.54 (2H, s), 6.96-7.03 (1H, m),7.39 (1H, m). 7.40-7.42 (2H, m), 7.51-7.56 (2H, m), 7.70 (1H, d, J=9Hz), 8.05 (1H, s);

6-Methoxy isomer: δ/ppm=2.19 (3H, s), 2.33 (3H, s), 3.74 (3H, s), 3.84(3H, s), 4.68 (2H, dd, J=13, 29 Hz), 5.53 (2H, s), 6.96-7.03 (1H, m),7.30 (1H, d, J=2 Hz), 7.40-7.42 (2H, m), 7.51-7.56 (2H, m), 7.76 (1H, d,J=9 Hz), 8.05 (1H, s).

EXAMPLE 4 Preparation of Amorphous Omeprazole Magnesium Salt

Magnesium metal (0.26 g) was added to methanol (60 mL) and stirred atroom temperature for 3-4 hours. To the mixture was added5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(10g) in portions. After stirring for 20-30 minutes the methanol wasevaporated to s small volume and ethyl acetate was added, which causedprecipitation. The damp cake obtained by filtration was pulped in ethylacetate for 2-3 hours. The suspension was filtered and cake wasvacuum-dried to afford omeprazole magnesium salt. Weight:7.0 g. Purity:99.5% by HPLC.

As many changes can be made to the preferred embodiments of theinvention without departing from the scope thereof, it is intended thatall matter contained herein be considered illustrative of the inventionand not in a limiting sense.

1. A process for preparing benzimidazoles of the formula (I):

wherein ring A is a benzene ring optionally having 1 to 3substituent(s), which may be the same or different, are eachindependently selected from (a) a halogen atom, (b) a cyano, (c) anitro, (d) an alkyl optionally having 1 to 3 substituent(s) selectedfrom a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxy carbonyl and acarbamoyl, (e) an alkoxy optionally having 1 to 3 substituent(s)selected from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and acarbamoyl, (f) an aryl, (g) an aryloxy, (h) an acyl, (i) an acyloxy and(j) a 5- to 10-membered heterocyclic group, R¹, R² and R³ are each ahydrogen atom; an alkyl group optionally having 1 to 3 substituent(s)selected from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and acarbamoyl; an alkoxy group optionally having 1 to 3 substituent(s)selected from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and acarbamoyl; or a di-C₆₋₁₄ arylamino, and * denotes a chiral center thatmay be present as a racemate or in optically enriched form depending onthe oxidation process used, or their pharmaceutically acceptable alkaliand alkaline earth salts, comprising: (i) oxidizing the correspondingsulfide of formula (II):

wherein A, R¹, R² and R³ have the definitions as for the compounds offormula I, (ii) acylating with an alkyl, aryl or aralkyl chloroformateand a base at the 1-N-atom of the sulfoxides's benzimidazole ring toproduce the derivatives of formula (III):

wherein A, R¹, R² and R³ is as for formula I and R⁴ is alkyl, aryl oraralkyl, (iii) adding the alkoxy-, aryloxy- or aralkoxycarbonyl compoundof formula III to: (a) a C1 to C4 alkyl alcohol, or (b) a solution of analkali metal alkoxide in a C1 to C4 alkyl alcohol, preferably in aquantity of about 1 mole per mole of the alkali metal, or (c) a solutionof an alkaline earth metal alkoxide in a C1 to C4 alkyl alcohol,preferably in a quantity of about 2 moles per mole of the alkaline earthmetal, and (iv) isolating the desired benzimidazole sulfoxide orbenzimidazole sulfoxide salt of formula I by precipitation by eitherconcentrating the solution and/or addition of an anti-solvent(s) and/orspray drying the solution.
 2. A process according to claim 1 wherein theoxidation step is an enantioselective oxidation.
 3. A process accordingto claim 1 wherein the prepared benzimidazole sulfoxide of formula (I)is one of lansoprazole, omeprazole, pantoprazole, or rabeprazole.
 4. Aprocess according to claim 2 wherein the prepared benzimidazolesulfoxide of formula (I) is an optically active form of lansoprazole,omeprazole, pantoprazole, or rabeprazole.
 5. A process for preparingomeprazole or its salts comprising: (i) oxidizing(2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole)to the corresponding sulfoxide,5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleusing an achiral oxidation process, (ii) acylating with an alkyl, arylor aralkyl chloroformate and a base at the N-atom of the sulfoxides'sbenzimidazole ring to produce the derivatives(5/6-methoxy-1-alkoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinyl]-1H-benzimidazole),(5/6-methoxy-1-aryloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinyl]-1H-benzimidazole),or(5/6-methoxy-1-aralkoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinyl]-1H-benzimidazole),(iii) adding the alkoxy-, aryloxy- or aralkoxycarbonyl derivative of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleto: (a) a C1 to C4 alkyl alcohol, or (b) a solution of an alkali metalalkoxide in a C1 to C4 alkyl alcohol, preferably in a quantity of about1 mole per mole of the alkali metal, or (c) a solution of an alkalineearth metal alkoxide in a C1 to C4 alkyl alcohol, preferably in aquantity of about 2 moles per mole of the alkaline earth metal, and (iv)isolating the desired omeprazole or omeprazole salt by precipitation byeither concentrating the solution and/or addition of an anti-solvent(s)and/or spray drying the solution.
 6. A process for preparingesomeprazole or its salts comprising: (i) enantioselectively oxidizing(2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole)to the corresponding sulfoxide,(S)-(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,(ii) acylating with an alkyl, aryl or aralkyl chloroformate and a baseat the N-atom of the sulfoxides's benzimidazole ring to produce theenantiomerically-enriched derivatives((S)-5/6-methoxy-1-alkoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinyl]-1H-benzimidazole),((S)-5/6-methoxy-1-aryloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinyl]-1H-benzimidazole),or((S)-5/6-methoxy-1-aralkoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinyl]-1H-benzimidazole),(iii) adding the alkoxy-, aryloxy- or aralkoxycarbonyl derivative of(S)-(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleto: (a) a C1 to C4 alkyl alcohol, or (b) a solution of an alkali metalalkoxide in a C1 to C4 alkyl alcohol, preferably in a quantity of about1 mole per mole of the alkali metal, or (c) a solution of an alkalineearth metal alkoxide in a C1 to C4 alkyl alcohol, preferably in aquantity of about 2 moles per mole of the alkaline earth metal, and (iv)isolating the desired esomeprazole or esomeprazole salt by precipitationby either concentrating the solution and/or addition of ananti-solvent(s) and/or spray drying the solution.
 7. A process accordingto claim 6 for the preparation of compounds of formula (IV):

wherein R⁴ is alkyl, aryl or aralkyl; and R⁵ is 5- or 6-methoxy.
 8. Aprocess, according to claim 7 for the preparation of mixtures of acompound of formula (IV) wherein R⁴ is alkyl, aryl or aralkyl; and R⁵ isa mixture of 5- and 6-methoxy.
 9. A process for the preparation of(S)-5-methoxy-1-tert-butoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleaccording to claim
 7. 10. A process for the preparation of(S)-6-methoxy-1-tert-butoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleaccording to claim
 7. 11. A process for the preparation of the mixtureof(S)-5-methoxy-1-tert-butoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand(S)-6-methoxy-1-tert-butoxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleaccording to claim
 8. 12. A process for the preparation of(S)-5-methoxy-1-benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleaccording to claim
 7. 13. A process for the preparation of(S)-6-methoxy-1-benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleaccording to claim
 7. 14. A process for the preparation of the mixtureof(S)-5-methoxy-1-benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand(S)-6-methoxy-1-benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleaccording to claim
 8. 15. A process according to claim 6 for thepreparation of a C1 to C4 alkyl alcohol solution containing esomeprazoleor its magnesium, sodium, potassium, lithium, or calcium salt.
 16. Aprocess according to claim 5 for the preparation of a C1 to C4 alkylalcohol solution containing omeprazole or its magnesium, sodium,potassium, lithium, or calcium salt.
 17. A process according to claim 15wherein the alcohol used is methanol, ethanol or iso-propanol.
 18. Aprocess according to claim 16 wherein the alcohol used is methanol,ethanol or iso-propanol.
 19. A process according to claim 17 wherein thealcohol used is methanol.
 20. A process according to claim 18 whereinthe alcohol used is methanol.
 21. A process according to claim 19wherein the alcohol solution contains esomeprazole magnesium.
 22. Aprocess according to claim 20 wherein the alcohol solution containsomeprazole magnesium.
 23. A process according to claim 19 wherein thealcohol solution contains esomeprazole sodium.
 24. A process accordingto claim 20 wherein the alcohol solution contains omeprazole sodium. 25.A process of preparation of esomeprazole or the magnesium, sodium,potassium, lithium or calcium salt form of esomeprazole by precipitationby concentrating the C1 to C4 alkyl alcohol solution and/or addition ofan anti-solvent or anti-solvents according to claim
 6. 26. A process ofpreparation of omeprazole or the magnesium, sodium, potassium, lithiumor calcium salt form of omeprazole by precipitation by concentrating theC1 to C4 alkyl alcohol solution and/or addition of an anti-solvent oranti-solvents according to claim
 5. 27. A process of preparation ofesomeprazole or the magnesium, sodium, potassium, lithium or calciumsalt form of esomeprazole by concentrating the methanol solutioncontaining esomeprazole or its corresponding salt and precipitatingusing an anti-solvent selected from C1 to C3 alkyl esters, C4 to C8alkyl ethers, and C5 to C9 hydrocarbons, and mixtures thereof accordingto claim
 25. 28. A process of preparation of omeprazole or themagnesium, sodium, potassium, lithium or calcium salt form of omeprazoleby concentrating the methanol solution containing omeprazole or itscorresponding salt and precipitating using an anti-solvent selected fromC1 to C3 alkyl esters, C4 to C8 alkyl ethers, and C5 to C9 hydrocarbons,and mixtures thereof according to claim
 26. 29. A process of preparationof esomeprazole or its magnesium, sodium, potassium, lithium or calciumsalt by concentrating the methanol solution containing esomeprazole orits corresponding salt and precipitating using ethyl acetate accordingto claim
 27. 30. A process of preparation of omeprazole or itsmagnesium, sodium, potassium, lithium or calcium salt by concentratingthe methanol solution containing omeprazole or its corresponding saltand precipitating using ethyl acetate according to claim
 28. 31. Aprocess of preparation of esomeprazole or its magnesium, sodium,potassium, lithium or calcium salt by concentrating the methanolsolution containing esomeprazole or its corresponding salt andprecipitating using methyl t-butyl ether according to claim
 27. 32. Aprocess of preparation of omeprazole or its magnesium, sodium,potassium, lithium or calcium salt by concentrating the methanolsolution containing omeprazole or its corresponding salt andprecipitating using methyl t-butyl ether according to claim
 28. 33. Aprocess of preparation of the esomeprazole magnesium salt in amorphousform according to claim
 6. 34. A process of preparation of theomeprazole magnesium salt in amorphous form according to claim
 5. 35. Anoptically active compound of formula (III):

wherein ring A is a benzene ring optionally having 1 to 3substituent(s), which may be the same or different, are eachindependently selected from (a) a halogen atom, (b) a cyano, (c) anitro, (d) an alkyl optionally having 1 to 3 substituent(s) selectedfrom a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxy carbonyl and acarbamoyl, (e) an alkoxy optionally having 1 to 3 substituent(s)selected from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and acarbamoyl, (f) an aryl, (g) an aryloxy, (h) an acyl, (i) an acyloxy and(j) a 5- to 10-membered heterocyclic group, R¹, R² and R³ are each ahydrogen atom; an alkyl group optionally having 1 to 3 substituent(s)selected from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and acarbamoyl; an alkoxy group optionally having 1 to 3 substituent(s)selected from a halogen atom, a C₁₋₆ alkoxy, a C₁₋₆ alkoxycarbonyl and acarbamoyl; or a di-C₆₋₁₄ arylamino, R⁴ is an alkyl, aryl or aralkylgroup, and * is an asymmetric center or their pharmaceuticallyacceptable alkali and alkaline earth salts.
 36. A compound of formula(IV):

wherein R⁴ is alkyl, aryl or aralkyl; and R⁵ is 5- or 6-methoxy.
 37. Amixture of a compound of formula (IV):

wherein R⁴ is alkyl, aryl or aralkyl; and R⁵ is 5- or 6-methoxy.
 38. Thecompound of claim 37 where R⁴ in formula (IV) is tert-butyl and R⁵ is5-methoxy.
 39. The compound of claim 37 where R⁴ in formula (IV) istert-butyl and R⁵ is 6-methoxy.
 40. The mixture of claim 37 where R⁴ informula (IV) is tert-butyl.
 41. The compound of claim 37 where R⁴ informula (IV) is benzyl and R⁵ is 5-methoxy.
 42. The compound of claim 37where R⁴ in formula (IV) is benzyl and R⁵ is 6-methoxy.
 43. The mixtureof claim 37 where R⁴ in formula (IV) is benzyl.